Bicyclic and tricyclic cannabinoids

ABSTRACT

Novel bicyclic-cannabinoids and hexahydrocannabinol analogs are presented. These compounds, when administered in a therapeutically effective amount to an individual or animal, results in a sufficiently high level of that compound in the individual or animal to cause a physiological response. The physiological response useful to treat a number of physiological conditions.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 10/483,482, filed Jul. 12, 2004 now U.S. Pat. No. 7,057,076,which is the U.S. National Phase of International Application No.PCT/US02/21961, filed Jul. 11, 2002, which claims the benefit of U.S.Provisional Application No. 60/305,228, filed Jul. 13, 2001, thecontents of each of which are incorporated herein by reference in theirentirety.

FIELD OF THE INVENTION

The present invention relates generally to cannabinoid analogs. Theinvention is more particularly concerned with new and improved bicyclicand tricyclic cannabinoids exhibiting high binding affinities forcannabinoid receptors, pharmaceutical preparations employing theseanalogs and methods of administering therapeutically effective amountsof the analogs to provide a physiological effect.

BACKGROUND OF THE INVENTION

The classical cannabinoid Δ⁹-Tetrahydrocannabinol (Δ⁹-THC) is the majoractive constituent extracted from Cannabis sativa. The effects ofcannabinoids are due to an interaction with specific high-affinityreceptors. Presently, two cannabinoid receptors have been characterized:CB1, a central receptor found in the mammalian brain and a number ofother sites in the peripheral tissues and CB2, a peripheral receptorfound principally in cells related to the immune system. The CB1receptor is believed to mediate the psychoactive properties, associatedwith classical cannabinoids. Characterization of these receptors hasbeen made possible by the development of specific synthetic ligands suchas the agonists WIN 55212-2 and CP 55,940.

In addition to acting at the cannabinoid receptors, cannabinoids such asΔ⁹-THC also affect cellular membranes, thereby producing undesirableside effects such as drowsiness, impairment of monoamine oxidasefunction and impairment of non-receptor mediated brain function. Theaddictive and psychotropic properties of some cannabinoids also limittheir therapeutic value.

The pharmacological effects of cannabinoids pertain to a variety ofareas such as the central nervous system, the cardiovascular system, theimmune system and/or endocrine system. More particularly, compoundspossessing an affinity for either the CB1 or the CB2 cannabinoidreceptors are useful as agents: acting on the central nervous system andimmunomodulators; in thymic disorders; vomiting; myorelaxation; varioustypes of neuropathy; memory disorders; dyskinesia; migraine; multiplesclerosis; asthma; epilepsy; glaucoma; in anticancer chemotherapy; inischemia and angor; in orthostatic hypotension; and in cardiacinsufficiency.

Currently known bicyclic-cannabinoids and hexahydrocannabinol analogscontain a linear alkyl side chain at the C-3 position. This linear alkylside chain at the C-3 position is a key pharmacophore in classicalcannabinoids and considered essential for cannabinoid receptor activity.Structure Activity Relationship (SAR) studies suggest that in knowncannabinoids, a 1,1-dimethylheptyl or a 1,2-dimethylheptyl side chain isoptimal for cannabinoid activity. Additionally, knownhexahydrocannabinol derivatives usually possess a carbonyl group in theC-9 position or a hydroxy group in the C-9 or C-11 positions. This“northern” functionality plays an important role on the cannabinoidstructure, associated with cannabimimetic activity. The presence of aC-9 carbonyl group or a C-9 or C-11 hydroxy group is also known tosignificantly enhance the potency of cannabinoids.

SUMMARY OF THE INVENTION

Briefly stated, one aspect of the present invention comprises novelbicyclic-cannabinoids and hexahydrocannabinol analogs, and theirphysiologically acceptable salts. In some variations the inventivehexahydrocannabinol analogs include hitherto unknown side chain moietiesat the C-3 position. In some variations the inventive hybrid typebicyclic-cannabinoids have terpene functionality combined with novelresorcinol moieties. The invention includes both the (−) and (+)enantiomers and all isomers. Some embodiments of this aspect arerepresented by the following compound formulas I, II, III, IV, V, VI.

Compound Formula I

wherein Y comprises >C═O, >CH—(CH₂)_(f)—Y₁—(CH₂)_(g)—Y₂, >C═N—Y₃,>CH—NY₄Y₅, >CH—(CH₂)_(h)—Y₆, —C(O)N(Y₇)—, —N(Y₇)C(O)—, >NY₁₁,>N—(CH₂)_(f)—Y₁—(CH₂)_(g)—Y₂, a spirocycle, or CY₉Y₁₀, including allisomers.

Y₁ independently comprises O, CO, C(O)O, OCO or CH₂.

Y₂ independently comprises H, halogen, CN, CF₃, N₃, OH, COOH, alkoxy,acyloxy, NCS, NCO or NY₇Y₈.

Y₃ independently comprises —OH, —NH₂, alkoxy, alkyl, —(CH₂)_(n)—NR₁₀R₁₁,—(CH₂)_(n)—CO₂R where R comprises H or alkyl, —O—(CH₂)_(n)—NR₁₀R₁₁,—O—(CH₂)_(n)—CO₂R or —O—(CH₂)_(n)—CONR₁₀R₁₁.

Y₄ independently comprises H, OH, alkoxy or alkyl.

Y₅ independently comprises H, OH, alkoxy or alkyl, wherein Y₄ and Y₅cannot both be OH and wherein Y₄ and Y₅ cannot both be alkoxy.

Y₆ independently comprises H, halogen, CN, COOH, COalkyl, CF₃, SO₂alkyl,COfluoroalkyl, N₃, OH, alkoxy, acyloxy, NCS, NCO or NY₇Y₈.

Y₇ independently comprises H, alkyl, hydroxyalkyl, an aromatic ring, anaromatic ring substituted by at least one member selected from alkyl,alkoxy, halogen and CF₃, a heterocyclic ring or a heteroaromatic ring.

Y₈ independently comprises H, alkyl, hydroxyalkyl, an aromatic ring, anaromatic ring substituted by at least one member selected from alkyl,alkoxy, halogen and CF₃, a heterocyclic ring or a heteroaromatic ring.Alternatively, Y₇ and Y₈ taken together comprise part of a 3 to 7membered saturated heterocyclic ring containing up to one additionalheteroatom selected from N, O and S.

Y₉ independently comprises H, alkyl or alkoxycarbonylmethyl.

Y₁₀ independently comprises H, alkyl or alkoxycarbonylmethyl.

Y₁₁ independently comprises H, alkyl, CO, CN, CO-alkyl, SO₂-akyl or CF₃.

f comprises an integer from 0 to about 5.

g comprises an integer from 0 to about 5.

h comprises an integer from 0 to about 5.

n comprises an integer from 0 to about 4.

R₁ and R₂ each independently comprise H, OH, halogen, alkyl, —O-alkyl,NH₂, NO₂, CN, acyl, aroyl, benzoyl, substituted benzoyl, arylalkyl,substituted arylalkyl, phenacyl, substituted phenacyl, —O-alkyl-NR₁₀R₁₁,—O-alkyl-COOR where R comprises H or alkyl, —O-alkyl-CONR₁₀R₁₁, OCOCH₃,—N(alkyl)₂, —CO(alkyl)X or —OCO(alkyl)X where X comprises H,dialkylamino, a cyclic amine, a carbocyclic ring, a heterocyclic ring,an aromatic ring or a heteroaromatic.

R₁₀ and R₁₁ each independently comprise H, alkyl, hydroxyalkyl or R₁₀and R₁₁ together comprise part of a 3 to 7 membered saturatedheterocyclic ring containing up to one additional heteroatom selectedfrom N, O and S.

R₃ comprises

wherein each Z independently comprises CR₁₂R₁₃ where R₁₂ and R₁₃ eachindependently comprise H, alkyl, S, O, NH, N(CH₃), SO or SO₂.

R₄ comprises —(CH₂)_(j)—R₅, —(CH₂)_(j)—A—(CH₂)_(k)—R₅ or—(CH₂)_(j)—A—(CH₂)_(k)—B—R₅.

-   -   A and B each independently comprise —CH₂—CH₂—, —CH═CH—, —C≡C—,        O, S, SO, SO₂ or NH.    -   R₅ comprises H, halogen, CN, CF₃, N₃, COOH, NH₂, N(CH₃)₂,        ⊕N(CH₃)₃, Sn(alkyl)₃, phenyl, COOR where R comprises H or alkyl,        a carbocylic ring, a heterocyclic ring, an aromatic ring, a        heteroaromatic ring, a polycarbocyclic ring structure having 2        to about 5 rings, a polyheterocyclic ring structure having 2 to        about 5 rings or CONR₁₀R₁₁ where R₁₀ and R₁₁ each independently        comprise H, alkyl, hydroxyalkyl or R₁₀ and R₁₁ together comprise        part of a 5 or 6 membered saturated heterocyclic ring containing        up to one additional heteroatom selected from N, O and S.

n comprises an integer from 0 to about 4.

j comprises an integer from 0 to about 7.

k comprises an integer from 0 to about 7.

In one variation of the invention R₃ comprises

wherein R₆ and R₇ each independently comprise H or alkyl.

R₈ comprises —(CH₂)_(j)—C≡C—(CH₂)_(k)—R₉.

-   -   R₉ comprises H, halogen, CN, CF₃, N₃, COOH, NH₂, N(CH₃)₂,        ⊕N(CH₃)₃, Sn(alkyl)₃, phenyl, COOR where R comprises H or alkyl,        a carbocylic ring, a heterocyclic ring, an aromatic ring, a        heteroaromatic ring, a polycarbocyclic ring structure having 2        to about 5 rings, a polyheterocyclic ring structure having 2 to        about 5 rings or CONR₁₀R₁₁ where R₁₀ and R₁₁ each independently        comprise H, alkyl, hydroxyalkyl or R₁₀ and R₁₁ together comprise        part of a 5 or 6 membered saturated heterocyclic ring containing        up to one additional heteroatom selected from N, O and S.    -   j comprises an integer from 0 to about 7.    -   k comprises an integer from 0 to about 7.

In another variation of the invention (compound formula II) R₁ and R₂each independently comprise H, OH, alkyl or alkoxy and R₃ comprises:

wherein R₁₃ and R₁₄ each independently comprise H or alkyl.

R₁₅ comprises H, halogen, CN, CF₃, N₃, COOH, NH₂, N(CH₃)₂, ⊕N(CH₃)₃,Sn(alkyl)₃, phenyl, COOR where R comprises H or alkyl, a carbocylicring, a heterocyclic ring, an aromatic ring, a heteroaromatic ring, apolycarbocyclic ring structure having 2 to about 5 rings, apolyheterocyclic ring structure having 2 to about 5 rings or CONR₁₀R₁₁where R₁₀ and R₁₁ each independently comprise H, alkyl, hydroxyalkyl orR₁₀ and R₁₁ together comprise part of a 5 or 6 membered saturatedheterocyclic ring containing up to one additional heteroatom selectedfrom N, O and S.

j comprises an integer from 0 to about 7.

k comprises an integer from 0 to about 7.

In another variation of the invention (compound formula II) Y comprises>CH—(CH₂)_(h)—Y₆.

Y₆ comprises I, CN or N₃ and h comprises an integer from about 1 toabout 3, or Y₆ comprises I or N₃ and h comprises an integer from 0 toabout 3.

R₁ and R₂ each independently comprise H, OH, alkyl or alkoxy.

R₃ comprises:

-   -   wherein R₁₆ comprises H, halogen, CN, CF₃, N₃, COOH, NH₂,        N(CH₃)₂, ⊕N(CH₃)₃, Sn(alkyl)₃, phenyl, COOR where R comprises H        or alkyl, a carbocylic ring, a heterocyclic ring, an aromatic        ring, a heteroaromatic ring, a polycarbocyclic ring structure        having 2 to about 5 rings, a polyheterocyclic ring structure        having 2 to about 5 rings or CONR₁₀R₁₁ where R₁₀ and R₁₁ each        independently comprise H, alkyl, hydroxyalkyl or R₁₀ and R₁₁        together comprise part of a 5 or 6 membered saturated        heterocyclic ring containing up to one additional heteroatom        selected from N, O and S.    -   n comprises an integer from 0 to about 7.

Another variation of the invention (compound formula IV) has thefollowing structure:

wherein X comprises >C═O, >CH—(CH₂)_(f)—X₁—(CH₂)_(g)—X₂, >C═N—X₃,>CH—NX₄X₅, >CH—(CH₂)_(h)—X₆, —C(O)N(X₇)—, —N(X₇)C(O)—, >NX₁₁,>N—(CH₂)_(f)—X₁—(CH₂)_(g)—X₂, a spirocycle, or CX₉X₁₀, including allisomers.

X₁ independently comprises O, CO, C(O)O, OCO or CH₂.

X₂ independently comprises H, halogen, CN, CF₃, N₃, OH, COOH, alkoxy,acyloxy, NCS, NCO or NX₇X₈.

X₃ independently comprises —OH, —NH₂, alkoxy, alkyl, —(CH₂)_(n)—NR₁₀R₁₁,—(CH₂)_(n)—CO₂R where R comprises H or alkyl, —O—(CH₂)_(n)—NR₁₀R₁₁,—O—(CH₂)_(n)—CO₂R or —O—(CH₂)_(n)—CONR₁₀R₁₁.

X₄ independently comprises H, OH, alkoxy or alkyl.

X₅ independently comprises H, OH, alkoxy or alkyl, wherein X₄ and X₅cannot both be OH and wherein X₄ and X₅ cannot both be alkoxy.

X₆ independently comprises H, halogen, CN, COOH, COalkyl, CF₃, SO₂alkyl,COfluoroalkyl, N₃, OH, alkoxy, acyloxy, NCS, NCO or NX₇X₈.

X₇ independently comprises H, alkyl, hydroxyalkyl, an aromatic ring, anaromatic ring substituted by at least one member selected from alkyl,alkoxy, halogen and CF₃, a heterocyclic ring or a heteroaromatic ring.

X₈ independently comprises H, alkyl, hydroxyalkyl, an aromatic ring, anaromatic ring substituted by at least one member selected from alkyl,alkoxy, halogen and CF₃, a heterocyclic ring or a heteroaromatic ring.

Alternatively, X₇ and X₈ taken together comprise part of a 3 to 7membered saturated heterocyclic ring containing up to one additionalheteroatom selected from N, O and S.

X₉ independently comprises H, alkyl or alkoxycarbonylmethyl.

X₁₀ independently comprises H, alkyl or alkoxycarbonylmethyl.

X₁₁ independently comprises H, alkyl, CO, CN, COalkyl, SO₂alkyl or CF₃.

f comprises an integer from 0 to about 3.

g comprises an integer from 0 to about 3.

h comprises an integer from 0 to about 3.

n comprises an integer from 0 to about 4.

R₁ independently comprises H, OH, halogen, alkyl, —O-alkyl, NH₂, NO₂,CN, acyl, aroyl, benzoyl, substituted benzoyl, arylalkyl, substitutedarylalkyl, phenacyl, substituted phenacyl, —O-alkyl-NR₁₀R₁₁,—O-alkyl-COOR where R comprises H or alkyl, —O-alkyl-CONR₁₀R₁₁, OCOCH₃,—N(alkyl)₂, —CO(alkyl)X or —OCO(alkyl)X where X comprises H,dialkylamino, a cyclic amine, a carbocyclic ring, a heterocyclic ring,an aromatic ring or a heteroaromatic.

R₁₀ and R₁₁ each independently comprise H, alkyl, hydroxyalkyl or R₁₀and

R₁₁ together comprise part of a 3 to 7 membered saturated heterocyclic

ring containing up to one additional heteroatom selected from N, O andS.

R₃ comprises

wherein each Z independently comprises CR₁₂R₁₃ where R₁₂ and R₁₃ eachindependently comprise H, alkyl, S, O, NH, N(CH₃), SO or SO₂.

R₄ comprises —(CH₂)_(j)—R₅, —(CH₂)_(j)—A—(CH₂)_(k)—R₅ or—(CH₂)_(j)—A—(CH₂)_(k)—B—R₅.

-   -   A and B each independently comprise —CH₂—CH₂—, —CH═CH—, —C≡C—,        O, S, SO, SO₂ or NH.    -   R₅ comprises H, halogen, CN, CF₃, N₃, COOH, NH₂, N(CH₃)₂,        ⊕N(CH₃)₃, Sn(alkyl)₃, phenyl, COOR where R comprises H or alkyl,        a carbocylic ring, a heterocyclic ring, an aromatic ring, a        heteroaromatic ring, a polycarbocyclic ring structure having 2        to about 5 rings, a polyheterocyclic ring structure having 2 to        about 5 rings or CONR₁₀R₁₁ where R₁₀ and R₁₁ each independently        comprise H, alkyl, hydroxyalkyl or R₁₀ and R₁₁ together comprise        part of a 5 or 6 membered saturated heterocyclic ring containing        up to one additional heteroatom selected from N, O and S.

n comprises an integer from 0 to about 4.

j comprises an integer from 0 to about 7.

k comprises an integer from 0 to about 7.

In one variation of the invention, R₃ comprises:

wherein R₆ and R₇ each independently comprise H or alkyl.

R₈ comprises —(CH₂)_(j)—C≡C—(CH₂)_(k)—R₉.

-   -   R₉ comprises H, halogen, CN, CF₃, N₃, COOH, NH₂, N(CH₃)₂,        ⊕N(CH₃)₃, Sn(alkyl)₃, phenyl, COOR where R comprises H or alkyl,        a carbocylic ring, a heterocyclic ring, an aromatic ring, a        heteroaromatic ring, a polycarbocyclic ring structure having 2        to about 5 rings, a polyheterocyclic ring structure having 2 to        about 5 rings or CONR₁₀R₁₁ where R₁₀ and R₁₁ each independently        comprise H, alkyl, hydroxyalkyl or R₁₀ and R₁₁ together comprise        part of a 5 or 6 membered saturated heterocyclic ring containing        up to one additional heteroatom selected from N, O and S.

j comprises an integer from 0 to about 7.

k comprises an integer from 0 to about 7.

In another variation of the invention (compound formula V) R₁ comprisesH, OH, alkyl or alkoxy and R₃ comprises:

wherein R₁₃ and R₁₄ each independently comprise H or alkyl.

-   -   R₁₅ comprises halogen, CN, CF₃, N₃, COOH, NH₂, N(CH₃)₂,        ⊕N(CH₃)₃, Sn(alkyl)₃, phenyl, COOR where R comprises H or alkyl,        a carbocylic ring, a heterocyclic ring, an aromatic ring, a        heteroaromatic ring, a polycarbocyclic ring structure having 2        to about 5 rings, a polyheterocyclic ring structure having 2 to        about 5 rings or CONR₁₀R₁₁ where R₁₀ and R₁₁ each independently        comprise H, alkyl, hydroxyalkyl or R₁₀ and R₁₁ together comprise        part of a 5 or 6 membered saturated heterocyclic ring containing        up to one additional heteroatom selected from N, O and S.    -   j comprises an integer from 0 to about 7.    -   k comprises an integer from 0 to about 7.

In another variation of the invention (compound formula VI) X comprises>CH—(CH₂)_(h)—X₆.

X₆ independently comprises I, CN, N₃ or COOH and h comprises an integerfrom about 1 to about 3, or X₆ comprises I, N₃ or COOH and h comprisesan integer from 0 to about 3, including all isomers.

R₁ independently comprises H, OH, alkyl or alkoxy.

R₃ comprises:

-   -   R₁₆ comprises H, halogen, CN, CF₃, N₃, COOH, NH₂, N(CH₃)₂,        ⊕N(CH₃)₃, Sn(alkyl)₃, phenyl, COOR where R comprises H or alkyl,        a carbocylic ring, a heterocyclic ring, an aromatic ring, a        heteroaromatic ring, a polycarbocyclic ring structure having 2        to about 5 rings, a polyheterocyclic ring structure having 2 to        about 5 rings or CONR₁₀R₁₁ where R₁₀ and R₁₁ each independently        comprise H, alkyl, hydroxyalkyl or R₁₀ and R₁₁ together comprise        part of a 5 or 6 membered saturated heterocyclic ring containing        up to one additional heteroatom selected from N, O and S.    -   n comprises an integer from 0 to about 7.

Unless otherwise specifically defined, “acyl” refers to the generalformula —C(O)alkyl.

Unless otherwise specifically defined, “acyloxy” refers to the generalformula —O-acyl.

Unless otherwise specifically defined, “alcohol” refers to the generalformula alkyl-OH.

Unless otherwise specifically defined, “alkyl” refers to a linear,branched or cyclic alkyl group having from 1 to about 9 carbon atomsincluding, for example, methyl, ethyl, propyl, butyl, hexyl, octyl,isopropyl, isobutyl, tert-butyl, cyclopropyl, cyclohexyl, cyclooctyl,vinyl and allyl. Unless otherwise specifically defined, an alkyl groupcan be saturated or unsaturated and substituted or unsubstituted. Unlessotherwise specifically limited, a cyclic alkyl group includesmonocyclic, bicyclic and polycyclic rings, for example norbornyl,adamantyl and related terpenes.

Unless otherwise specifically defined, “alkoxy” refers to the generalformula —O-alkyl.

Unless otherwise specifically defined, “alkylmercapto” refers to thegeneral formula —S-alkyl.

Unless otherwise specifically defined, “alkylamino” refers to thegeneral formula —(NH)-alkyl.

Unless otherwise specifically defined, “di-alkylamino” refers to thegeneral formula —N-(alkyl)₂. Unless otherwise specifically limiteddi-alkylamino includes cyclic amine compounds such as piperidine andmorpholine.

Unless otherwise specifically defined, an aromatic ring is anunsaturated ring structure having about 5 to about 6 ring members andincluding only carbon as ring atoms. Unless otherwise specificallydefined, an aromatic ring can be substituted or unsubstituted.

Unless otherwise specifically defined, “aryl” refers to an aromatic ringsystem substituted or unsubstituted, that includes only carbon as ringatoms, for example phenyl, biphenyl or napthyl.

Unless otherwise specifically defined, “aroyl” refers to the generalformula —C(═O)-aryl.

Unless otherwise specifically defined, a carbocyclic ring is a ringstructure having about 3 to about 8 ring members, substituted orunsubstituted, that includes only carbon as ring atoms, for example,benzene or cyclohexane.

Unless otherwise specifically defined, “halogen” refers to an atomselected from fluorine, chlorine, bromine and iodine.

Unless otherwise specifically defined, a heteroaromatic ring is anunsaturated ring structure having about 5 to about 8 ring members,substituted or unsubstituted, that has carbon atoms and one or moreheteroatoms, including oxygen, nitrogen and/or sulfur, as ring atoms,for example, pyridine, furan, quinoline, and their derivatives.

Unless otherwise specifically defined, a heterocyclic ring is asaturated ring structure having about 3 to about 8 ring members,substituted or unsubstituted, that has carbon atoms and one or moreheteroatoms, including oxygen, nitrogen and/or sulfur, as ring atoms,for example, piperidine, morpholine, piperazine, and their derivatives.Unless otherwise specifically limited a heterocyclic ring includesmonocyclic, bicyclic and polycyclic rings, for example azaadamantyl andtropanyl.

Unless otherwise specifically defined, the term “phenacyl” refers to thegeneral formula—phenyl-acyl.

Unless otherwise specifically defined, a spirocycle refers to a ringsystem wherein a single atom is the only common member of two rings. Aspirocycle can comprise a saturated carbocyclic ring comprising about 3to about 8 ring members, a heterocyclic ring comprising about 3 to about8 ring atoms wherein up to about 3 ring atoms may be N, S, or O or acombination thereof.

Substituent groups for the above moieties useful in the invention arethose groups that do not significantly diminish the biological activityof the inventive compound. Substituent groups that do not significantlydiminish the biological activity of the inventive compound include, forexample, —OH, —NH₂, halogen, —CN, —NO₂, —NHalkyl, —N(alkyl)₂, —CF₃,—NCS, azido, —CONHalkyl, —NHCOalkyl, sulfonamide, alkyl, alkoxy,thioalkoxy and alcohol.

Testing of the inventive compounds for their affinities for the central(CB1) and peripheral (CB2) cannabinoid receptors, showed a high affinityfor the two cannabinoid receptors. Thus, another aspect of the inventionis use of at least one of the inventive compounds, and physiologicallyacceptable salts thereof, to stimulate cannabinoid receptors.

Some of the inventive analogs showed high selectivity for the CB2receptor. These inventive CB2 selective analogs are able to stimulatethe CB2 receptor without affecting the central (CB1) receptor to thesame degree. Therefore, another aspect of the invention is use of atleast one of the inventive compounds, and physiologically acceptablesalts thereof, to preferentially stimulate the CB2 receptor.

The inventive bicyclic-cannabinoids and hexahydrocannabinol analogsdescribed herein, and physiologically acceptable salts thereof, havepharmacological properties when administered in therapeuticallyeffective amounts for providing a physiological effect useful to treatcentral and peripheral pain, neuropathy, neurodegenerative diseasesincluding multiple sclerosis, Parkinson's disease, Huntington's chorea,Alzheimer's disease; mental disorders such as schizophrenia anddepression; to prevent or reduce endotoxic shock and hypotensive shock;to modulate appetite; to modulate the immune system; to reducefertility; to prevent or reduce diseases associated with motor functionsuch as Tourette's syndrome; to prevent or reduce inflammation; toprovide neuroprotection and to suppress memory and produce peripheralvasodilation; to treat epilepsy, glaucoma, nausea associated with cancerchemotherapy and AIDS wasting syndrome as well as other ailments inwhich cannabinoid system is implicated. Thus, another aspect of theinvention is the administration of a therapeutically effective amount ofan inventive compound, or a physiologically acceptable salt thereof, toan individual or animal to provide a physiological effect.

DESCRIPTION OF SOME PREFERRED EMBODIMENTS

As used herein a “therapeutically effective amount” of a compound, isthe quantity of a compound which, when administered to an individual oranimal, results in a discernible physiological effect in the individualor animal. The inventive compounds described herein, and physiologicallyacceptable salts thereof, have pharmacological properties whenadministered in therapeutically effective amounts for providing aphysiological effect useful to treat a number of physiologicalconditions.

Typically, a “therapeutically effective amount” of an inventive compoundis believed to range from about 5 mg/day to about 1,000 mg/day.

As used herein, an “individual” refers to a human. An “animal” refersto, for example, veterinary animals, such as dogs, cats, horses and thelike, and farm animals, such as cows, pigs and the like.

The compound of the present invention can be administered by a varietyof known methods, including, for example, orally, rectally, or byparenteral routes (e.g., intramuscular, intravenous, subcutaneous, nasalor topical). The form in which the compounds are administered will bedetermined by the route of administration. Such forms include, but arenot limited to, capsular and tablet formulations (for oral and rectaladministration), liquid formulations (for oral, intravenous,intramuscular, subcutaneous, ocular, intranasal, inhalation-based andtransdermal administration) and slow releasing microcarriers (forrectal, intramuscular or intravenous administration). The formulationscan also contain a physiologically acceptable vehicle and optionaladjuvants, flavorings, colorants and preservatives. Suitablephysiologically acceptable vehicles include, for example, saline,sterile water, Ringer's solution and isotonic sodium chloride solutions.The specific dosage level of active ingredient will depend upon a numberof factors, including, for example, biological activity of theparticular preparation, age, body weight, sex and general health of theindividual being treated.

In one aspect of the invention the inventive compounds are generallyrepresented by compound formulas I, II, III, IV, V, VI and includephysiologically acceptable salts thereof.

Compound Formulas I-VI

Some inventive analogs were tested for CB2 receptor binding affinity andfor CB1 receptor affinity (to determine selectivity). As used herein,“binding affinity” is represented by the IC₅₀ value which is theconcentration of an analog required to occupy the 50% of the totalnumber (Bmax) of the receptors. The lower the IC₅₀ value the higher thebinding affinity. As used herein an analog is said to have “bindingselectivity” if it has higher binding affinity for one receptor comparedto the other receptor; e.g. a cannabinoid analog which has an IC₅₀ of0.1 nM for CB1 and 10 nM for CB2, is 100 times more selective for theCB1 receptor. For the CB1 receptor binding studies, membranes wereprepared from rat forebrain membranes according to the procedure of P.R. Dodd et al, A Rapid Method for Preparing Synaptosomes: Comparisonwith Alternative Procedures, Brain Res., 107-118 (1981). The binding ofthe novel analogues to the CB1 cannabinoid receptor was assessed asdescribed in W. A. Devane et al, Determination and Characterization of aCannabinoid Receptor in a Rat Brain, Mol. Pharmacol., 34, 605-613 (1988)and A. Charalambous et al, 5′-azido Δ ⁸- THC: A Novel PhotoaffinityLabel for the Cannabinoid Receptor, J. Med. Chem., 35, 3076-3079 (1992)with the following changes. The above articles are incorporated byreference herein.

Membranes, previously frozen at −80° C., were thawed on ice. To thestirred suspension was added three volumes of TME (25 mM Tris-HClbuffer, 5 mM MgCl₂ and 1 mM EDTA) at a pH 7.4. The suspension wasincubated at 4° C. for 30 min. At the end of the incubation, themembranes were pelleted and washed three times with TME.

The treated membranes were subsequently used in the binding assaydescribed below. Approximately 30 μg of membranes were incubated insilanized 96-well microtiter plate with TME containing 0.1% essentiallyfatty acid-free bovine serum albumin (BSA), 0.8 nM [³H] CP-55,940, andvarious concentrations of test materials in a final volume of 200 μL.The assays were incubated for 1 hour at 30° C. and then immediatelyfiltered using Packard Filtermate 196 harvester and Whatman GF/Cfilterplates and washed with wash buffer (TME) containing 0.5% BSA.Radioactivity was detected using MicroScint 20 scintillation cocktailadded directly to the dried filterplates, and the filterplates werecounted using a Packard Instruments Top-Count. Nonspecific binding wasassessed using 100 nM CP-55,940. Data collected from three independentexperiments performed with duplicate determinations was normalizedbetween 100% and 0% specific binding for [³H] CP-55,940, determinedusing buffer and 100 nM CP-55,940. The normalized data was analyzedusing a 4-parameter nonlinear logistic equation to yield IC₅₀ values.Data from at least two independent experiments performed in duplicatewas used to calculate IC₅₀ values which were converted to K_(i) valuesusing the assumptions of Cheng et al, Relationship Between theInhibition Constant (K _(i)) and the concentration of Inhibitor whichcauses 50% Inhibition (IC ₅₀) of an Enzymatic Reaction, Biochem.Pharmacol., 22, 3099-3102, (1973), which is incorporated by referenceherein.

For the CB2 receptor binding studies, membranes were prepared fromfrozen mouse spleen essentially according to the procedure of P. R. Doddet al, A Rapid Method for Preparing Synaptosomes: Comparison withAlternative Procedures, Brain Res., 226, 107-118 (1981) which isincorporated by reference herein. Silanized centrifuge tubes were usedthroughout to minimize receptor loss due to adsorption. The CB2 bindingassay was conducted in the same manner as for the CB1 binding assay. Thebinding affinities (K_(i)) were also expressed in nanomoles (nM). Someof the synthesized analogs disclosed below exhibited a selectivity forthe CB2 receptor of from less than 10 fold to about 500 fold. Some ofthe synthesized analogs disclosed below exhibited a lesser selectivityfor the CB1 receptor.

The following examples are given for purposes of illustration only inorder that the present invention may be more fully understood. Theseexamples are not intended to limit in any way the scope of the inventionunless otherwise specifically indicated.

EXAMPLES

Bicyclic-cannabinoid hybrids of compound formula I, II and III weresynthesized with different R groups and different Y, B, Gfunctionalities are depicted in Table 1. The CB1 and CB2 bindingaffinity value (Ki) for the synthesized analogs range between 31-224 nMand 0.2-77 nM respectively.

TABLE 1 Novel Bicyclic-cannabinoid analogs of compound formula I, II andIII. Ki in nM Ki in nM for the for the Compound Y CB1 CB2 numberFunctionality R₁ R₂ R₃ Receptor Receptor 2a

OH OH

50.6 0.4 2b

OH OH

74.5 0.4 2c

OH OH

223.5 10.9 2d

OH OH

10.6 9.3 2e

OH OH

30.8 0.2 3

OH OH

133.2 76.8

Hexahydrocannabinol derivatives of compound formula IV, V and VI weresynthesized with different R groups and different X, Q, Mfunctionalities are depicted in Table 2. The CB1 and CB2 bindingaffinity value (Ki) for the synthesized analogs range between 0.1-12 nMand 0.2-14 nM respectively.

TABLE 2 Novel Hexahydrocannabinol analogs of compound formula IV, V andVI. Ki in nM for the Ki in nM for Compound X CB1 the CB2 numberFunctionality R₁ R₃ Receptor Receptor 4a

OH

0.1 2.6 4b

OH

0.2 0.2 4c

OH

11.7 2.3 4d

OH

1.0 11.8 4e

OH

10.7 4.1 5

OH

4.5 13.9 6d

OH

— — 6e

OH

11.3 12 6f

OH

— — 7d

OH

1.6 13.7 7f

OH

— — 7g

OH

5.0 10.2 8

OH

0.8 0.9 9

OH

0.7 0.7

Preparation of Compounds of Compound Formula I, II, III

1. Resorcinol Synthesis

Resorcinol compounds 1a and 1b (shown in Scheme 1) were synthesized by amethod depicted in Scheme 1, starting from(3,5-dimethoxyphenyl)cyclopentane carboxaldehyde, which was prepared bythe method disclosed in Papahatjis et al. Chemistry Letters, 192 (2001),the content of which is hereby incorporated by reference.

General Procedure:

(Butylmethylene) triphenylphosphorane

To a suspension of pentyltriphenylphosphonium bromide (5 equiv.) in dryTHF (0.18M) at 0° C., under an argon atmosphere was added potassiumbis(trimethylsilyl) amide (4.9 equiv.). The mixture was warmed to 10° C.and stirred for an additional 30 min to ensure complete formation of theorange ylide. The resulting slurry was used in the preparation of1-(3,5-dimethoxyphenyl)-1-(hex-1-enyl)-cyclopentane.

1-(3,5-Dimethoxyphenyl)-1-(hex-1-enyl)-cyclopentane

To the above slurry of (butylmethylene) triphenylphosphorane at 10° C.under an argon atmosphere was added dropwise a solution of(3,5-dimethoxyphenyl)cyclopentane carboxaldehyde (1 equiv.) in dry THF(0.21M). The reaction was stirred for 45 min and upon completion wasquenched by the addition of saturated aqueous ammonium chloride. Theorganic layer was separated and the aqueous phase was extracted twicewith diethyl ether. The combined organic layer was washed with brine,dried over MgSO₄ and the solvent was evaporated under reduced pressureto give an oil. The crude product was purified through a short column ofsilica gel using 5% diethyl ether-petroleum ether as eluent to affordthe title compound in 96% yield.

1-(3,5-Dimethoxyphenyl)-1-hexyl-cyclopentane

To a solution of 1-(3,5-dimethoxyphenyl)-1-(hex-1-enyl)-cyclopentane (1equiv.) in ethyl acetate (0.11M) was added 10% Pd/C (17%, w/w) and theresulting suspension was stirred vigorously under an hydrogenatmosphere, overnight at room temperature. The catalyst was removed byfiltration through celite and the filtrate was evaporated under reducedpressure to afford the crude product. Purification through a shortcolumn of silica gel using 5% diethyl ether-petroleum ether yielded thetitle compound in 95% yield.

5-(1-Hexyl-cyclopentyl)resorcinol, (Compound 1a)

To a solution of 1-(3,5-dimethoxyphenyl)-1-hexyl-cyclopentane (1 equiv.)in dry methylene chloride (0.04M) at −78° C. under an argon atmospherewas added boron tribromide (2.5 equiv., 1M solution in methylenechloride). Following the addition, the reaction temperature wasgradually raised over a period of 3 h to −20° C. Stirring was continuedat that temperature until completion of the reaction. Unreacted borontribromide was destroyed by addition of methanol and ice at 0° C. Theresulting mixture was warmed at room temperature, stirred for 40 min andthe solvent was removed in vacuo. The residual oil was diluted withethyl acetate and the solution was washed with saturated sodiumbicarbonate, water and brine. The organic layer was dried over MgSO₄,filtered and concentrated under reduced pressure. Purification by flashcolumn chromatography (40% diethyl ether-petroleum ether as eluent)afforded the title compound in 90% yield.

¹H NMR (500 MHz, CDCl₃) δ: 6.36 (d, J=1.6 Hz, 2H), 6.19 (t, J=1.6 Hz,1H), 5.78 (brs, 2H, OH), 1.83-1.77 (m, 2H), 1.73-1.58 (m, 6H), 1.51-1.48(m, 2H), 1.22-1.12 (m, 6H), 1.02-0.94 (m, 2H), 0.83 (t, J=7.1 Hz, 3H).

5-[1-(Hex-1-enyl)-cyclopentyl]resorcinol, (Compound 1b)

To a solution of 1-(3,5-dimethoxyphenyl)-1-(hex-1-enyl)-cyclopentane (1equiv.) in dry hexane (0.05 M) at 0° C. under an argon atmosphere wasadded 9-iodo-9-BBN (2.3 equiv., 1M solution in hexane). The mixture wasstirred at the same temperature for 3.5 h and then the reactiontemperature was raised to 27° C. Stirring was continued at thattemperature until completion of the reaction. The volatiles were removedin vacuo, the residual oil was dissolved in diethyl ether, and asolution of ethanolamine (2.4 equiv.) in THF (1.4 M) was added causingspontaneous precipitation of the 9-BBN.ethanolamine adduct. Thesuspension was stirred for 2.5 h, the white precipitate was filtered offand the filtrate was evaporated under reduced pressure to give an oil.Purification by flash column chromatography on silica gel using 40%diethyl ether-petroleum ether as eluent afforded the title compound in82% yield.

¹H NMR (500 MHz, CDCl₃) δ: 6.44 (d, J=1.9 Hz, 2H), 6.17 (t, J=1.9 Hz,1H), 5.66 (d, J=11.0 Hz, 1H), 5.28(dt, J=11.0 Hz, J=7.3 Hz, 1H),5.14(brs, 2H, OH), 2.01-1.85(m, 4H), 1.80-1.65(m, 6H), 1.15-1.07(m, 4H),0.77(t, J=6.8 Hz, 3H).

Resorcinol compound 1c (shown in Scheme 3) was synthesized by the methoddisclosed in Papahatjis et al. J. Med. Chem., 41: 1195-1200 (1998), thecontent of which is hereby incorporated by reference. Resorcinolcompound 1d (shown in Scheme 3) was synthesized by the method disclosedin Yan Guo et al. J. Med. Chem., 37: 3867-3870 (1994), the content ofwhich is hereby incorporated by reference.

Resorcinol compound 1e (shown in Scheme 2) was synthesized by the methoddepicted in Scheme 2.

General Procedure:

[7-(3,5-Dimethoxyphenyl-1,3-dithian-7-yl)-1-heptynyl]trimethylsilane

A solution of 2-(3,5-dimethoxyphenyl)-1,3-dithiane (1 equiv.) in drytetrahydrofuran (0.5 M) was cooled to −30° C. under argon andn-butyllithium (1.2 equiv., 1.6 M solution in hexanes) was addeddropwise. The yellow-brown reaction mixture was stirred at the sametemperature for 2 hours and (6-bromo-1-hexynyl)trimethylsilane (1.2equiv.) was added in a dropwise manner when the color changed fromyellow-brown to light yellow. The reaction mixture was allowed to warmto room temperature overnight and poured into water and extracted withdiethyl ether. The combined organic extracts were dried and etherremoved to give the crude product which was purified on silica gel (15%diethyl ether-petroleum ether) to afford the title compound in 86% yieldas an oil.

Anal. calcd. for C₂₁H₃₂O₂S₂Si C, 61.72; H, 7.89; found C, 61.49; H,8.24.

[7-(3,5-Dimethoxyphenyl)-7-oxo-1-heptynyl]trimethylsilane

A solution of[7-(3,5-dimethoxyphenyl-1,3-dithian-7-yl)-1-heptynyl]trimethylsilane (1equiv.) in 10% aqueous methanol (0.1 M) was cooled in an ice-bath andbis(trifluoroacetoxy)iodobenzene (1.5 equiv.) was added portionwise withstirring. The reaction mixture was stirred for an additional 10 min andpoured into sodium bicarbonate solution. The mixture was extracted withdiethyl ether, ether extracts were combined, dried and solvent removedto afford an oil which was chromatographed on silica gel to afford thetitle compound in 90% yield.

Anal. calcd. for C₁₈H₂₆O₃Si C, 67.88; H, 8.23; found C, 67.56; H, 8.55

[7-(3,5-Dimethoxyphenyl)-7-methyl-1-octynyl]trimethylsilane

[7-(3,5-Dimethoxyphenyl)-7-oxo-1-heptynyl]trimethylsilane (1 equiv.) wasdissolved in anhydrous ether (0.5 M), the solution was cooled in anice-bath under argon and methylmagnesium bromide (2 equiv., 3M solutionin diethyl ether) was added dropwise. The light gray solution wasallowed to warm to room temperature and stirred for an additional hour.The reaction mixture was poured into saturated ammonium chloridesolution, the organic phase was separated and the aqueous phase wasextracted with diethyl ether. The combined organic extracts were driedand ether removed to afford pure[7-(3,5-dimethoxyphenyl)-7-hydroxy-1-octynyl]trimethylsilane as aviscous oil after passing through a short silica gel column, in 95%yield.

The above tertiary carbinol (1 equiv.) was dissolved in anhydrous carbontetrachloride (0.5 M) and dry hydrogen chloride gas was bubbled throughfor 1 hour. The solution was transferred to a separatory funnel with theaid of more carbon tetrachloride, washed with water and 10% sodiumbicarbonate solution. The organic phase was dried and rotary evaporatedto afford an oil which was passed through a short silica gel column togive pure [7-chloro-7-(3,5-dimethoxyphenyl)-1-octynyl]trimethylsilane.

A solution of the above chloride (1 equiv.) in dry toluene was cooled to−30° C. under argon and trimethylaluminum (2 equiv., 2M solution intoluene) was added in a slow dropwise manner. The resulting clearreaction mixture was stirred at room temperature for about 16 hours andthen 5% aqueous hydrochloric acid was added in a very cautious manner.The organic layer was separated, washed with water, dried and tolueneremoved. The residual oil was chromatographed on silica gel to affordthe title compound as colorless oil.

¹H NMR (CDCl₃) δ 6.47 (d, J=2.16 Hz, 2H), 6.28 (t, J=2.16 Hz, 1H), 3.78(s, 6H), 2.14 (t, J=7.08 Hz, 2H), 1.63-1.06 [overlapping patterns i.e.,1.63-1.06 (m, 6H), 1.25 (s, 6H)], 0.10 (s, 9H). Anal. calcd. forC₂₀H₃₂O₂Si C, 72.23; H, 9.70; found C, 71.98; H, 9.87.

7-(3,5-Dimethoxyphenyl)-7-methyl-1-octyne

[7-(3,5-Dimethoxyphenyl)-7-methyl-1-octynyl]trimethylsilane (1 equiv.)was dissolved in anhydrous methanol (0.8 M), anhydrous potassiumcarbonate (0.2 equiv.) was added and the heterogeneous mixture wasstirred at room temperature, under argon, for 24 hours. The reactionmixture was diluted with water and extracted with diethyl ether. Theether extract was dried, concentrated by rotary evaporation and theresidue was purified by chromatography on silica gel (5% diethylether-petroleum ether) to give the title compound in 76% yield.

3-(1,1-Dimethylhept-6-ynyl)resorcinol, (Compound 1e)

A solution of 7-(3,5-dimethoxyphenyl)-7-methyl-1-octyne (1 equiv.) inanhydrous dichloromethane (0.1 M) was cooled to −40° C. under argon andboron tribromide (2.5 equiv., 1M solution in dichloromethane) was addedvia syringe. The reaction mixture was allowed to warm to 0° C. withstirring over a period of 1-1.5 hours and then quenched with saturatedsodium bicarbonate. The organic layer was separated, dried and solventremoved. The residue was chromatographed on silica gel (30-40% diethylether-petroleum ether) to give the title resorcinol in 56% yield.

¹³C NMR (CDCl₃) δ 156.37, 153.11, 105.92, 100.11, 84.76, 68.22, 55.30,43.77, 37.70, 29.03, 28.79, 23.87, 18.24.

2. Bicyclic Cannabinoid Synthesis

The bicyclic ketones (compound 2 with, for example, R groups a, b, c, dor e shown in Scheme 3) were synthesized by the method depicted inScheme 3.

General Procedure:

To a solution of resorcinol (1 equiv.) and nopinone diacetates(approximately 1.3 equiv., ca. 87% pure by ¹H NMR) in chloroform(approximately 0.1M) at 0° C. was added p-toluene sulfonic acidmonohydrate (approximately 1.3 equiv.). Following the addition, thereaction temperature was raised to room temperature and stirring wascontinued for 4 hours to 3 days to ensure complete formation of theproduct. The reaction mixture was diluted with an organic solvent andwashed sequentially with water, saturated aqueous sodium bicarbonate,and brine. The organic phase was dried over MgSO₄ and the solvent wasremoved under reduced pressure. The residue was chromatographed onsilica gel to afford the bicyclic ketone.

Compound 2a

(4R)-4-[4-(1′,1′-cyclopentylheptyl)-2,6-dihydroxyphenyl]-6,6-dimethyl-2-norpinanone.Yield: 49%; white solid; mp=187-188° C.

Compound 2b

(4R)₄-[4-(1′,1′-cyclopentylhept-2′-enyl)-2,6-dihydroxyphenyl]-6,6-dimethyl-2-norpinanone.Yield: 47%; white solid; mp=167-168° C.

Compound 2c

(4R)-4-[4-(2-hexyl-1,3-dithiolan-2-yl)-2,6-dihydroxyphenyl]-6,6-dimethyl-2-norpinanone.Yield: 13%; white solid; mp=160-161° C. dec.

¹H NMR (500 MHz, CDCl₃) δ: 6.68(s, 2H, ArH), 5.02(brs, 2H, OH), 3.95(t,J=8.2 Hz, 1H), 3.44 (dd, J=18.7 Hz, J=7.8 Hz, 1H), 3.37-3.30 (m, 2H),3.25-3.18 (m, 2H), 2.60 (dd, J=19.5 Hz, J=8.5 Hz, 1H), 2.58 (t, J=4.7Hz, 1H), 2.53-2.49 (m, 1H), 2.44 (d, J=10.8 Hz, 1H), 2.30 (m, 1H),2.26-2.22 (m, 2H), 1.36 (s, 3H), 1.27-1.19 (m, 8H), 0.99 (s, 3H), 0.85(t, J=6.5 Hz, 3H).

Compound 2d

(4R)4-[4-(7′-bromo-1′,1′-dimethylheptyl)-2,6-dihydroxyphenyl]-6,6-dimethyl-2-norpinanone.Yield: 41%; light yellow solid. The title compound (2d) was used in thepreparation of the derivative compound 4d.

Anal. calcd. for C₂₄H₃₄BrO₂ C, 63.85; H, 7.81; found C, 63.99; H, 8.20.

Compound 2e

(4R)-4-[4-(1′,1′-dimethylhept-6′-ynyl)-2,6-dihydroxyphenyl]-6,6-dimethyl-2-norpinanone.Yield: 40%. The title compound (2e) was used in the preparation of thederivative compound 4e.

FAB HRMS calcd for C₂₄H₃₂O₃ 369.2430 (M+H⁺); found 369.2430.

Compound 3

Synthesis of a diastereomeric mixture of(4R)4-[4-(2-hexyl-1,3-dithiolan-2-yl)-2,6-dihydroxyphenyl]-6,6-dimethyl-2β-norpinanoland(4R)-4-[4-(2-hexyl-1,3-dithiolan-2-yl)-2,6-dihydroxyphenyl]-6,6-dimethyl-2α-norpinanol.

The title mixture (compound 3) was synthesized by the method depicted inScheme 4 below.

Procedure:

To a stirred solution of(4R)-4-[4-(2-hexyl-1,3-dithiolan-2-yl)-2,6-dihydroxyphenyl]-6,6-dimethyl-2-norpinanone(compound 2c) (11 mg, 0.025 mmol) in methanol (0.5 ml) at −15° C. underan argon atmosphere was added sodium borohydride (3 mg 0.079 mmol). Thereaction was stirred at the same temperature for 2.5 hours and uponcompletion was quenched by the addition of saturated aqueous ammoniumchloride. The volatiles were removed in vacuo and the residue wasextracted with ethyl acetate. The organic layer was washed with waterand brine, dried over MgSO₄ and the solvent evaporated. The residue waschromatographed on silica gel to afford 6 mg (54%) of the title mixtureas a white glassy.

Preparation of Compounds of Compound Formula IV, V, VI

3. 9-Nor-9-oxohexahydrocannabinol Synthesis

The 9-Nor-9-oxohexahydrocannabinols (compound 4 with, for example, Rgroups a, b, c, d and e shown in Scheme 5) were synthesized by themethod depicted in Scheme 5.

General Procedure:

To a stirred solution of bicyclic ketone (1 equiv.) in a mixture of drymethylene chloride-nitromethane (approximately 0.01-0.05M) at 0° C.,under an argon atmosphere was added trimethylsilyltrifluoromethanesulfonate (approximately 0.3-1.3 equiv.). Following theaddition, the mixture was stirred from 0° C. to room temperature for 1-7hours. The reaction was quenched with saturated aqueous sodiumbicarbonate/brine (1:1), and organic solvent was added. The organicphase was separated, the aqueous phase was extracted with organicsolvent, and the combined organic phase was washed with brine and driedover MgSO₄. Solvent evaporation followed by flash column chromatographyon silica gel afforded 9-Nor-9-oxohexahydrocannabinols.

Compound 4a

(−)-trans-3-(1′,1′-cyclopentylheptyl)-6,6a,7,8,10,10a-hexahydro-1-hydroxy-6,6-dimethyl-9H-dibenzo[b,d]pyran-9-one.Yield: 75%; White foam.

Compound 4b

(−)-trans-3-(1′,1′-cyclopentylhept-2′-enyl)-6,6a,7,8,10,10a-hexahydro-1-hydroxy-6,6-dimethyl-9H-dibenzo[b,d]pyran-9-one.Yield: 73%; White foam.

Compound 4c

(−)-trans-3-(2-hexyl-1,3-dithiolan-2-yl)-6,6a,7,8,10,10a-hexahydro-1-hydroxy-6,6-dimethyl-9H-dibenzo[b,d]pyran-9-one.Yield: 83%; White foam; mp=62-64° C. dec.

¹H NMR (500 MHz, CDCl₃) δ: 6.76 (d, J=1.8 Hz, 1H, ArH), 6.64 (d, J=1.8Hz, 1H, ArH), 5.85 (s, 1H, OH), 3.94 (d, J=14.6 Hz, 1H), 3.36-3.30 (m,2H), 3.28-3.21 (m, 2H), 2.87 (td, J=11.9 Hz, J=3.3 Hz, 1H), 2.63-2.59(m, 1H), 2.48-2.40 (m, 1H), 2.27 (m, 2H), 2.18-2.14 (m, 2H), 1.96 (td,J=11.7 Hz, J=2.0 Hz, 1H), 1.56-1.45 (m, 4H), 1.26-1.19 (m, 8H), 1.12 (s,3H), 0.84 (t, J=7.0 Hz, 3H).

Compound 4d

(−)-trans-3-(7′-bromo-1′,1′-dimethylheptyl)-6,6a,7,8,10,10a-hexahydro-1-hydroxy-6,6-dimethyl-9H-dibenzo[b,d]pyran-9-one.Yield: 71%; light yellow foam. The title compound (4d) was used in thepreparation of the derivative compound 6d.

Anal. calcd. for C₂₄H₃₄BrO₂ C, 63.85; H, 7.81; found C, 63.99; H, 8.20.

Compound 4e

(−)-trans-3-(1′,1′-dimethylhept-6′-ynyl)-6,6a,7,8,10,10a-hexahydro-1-hydroxy-6,6-dimethyl-9H-dibenzo[b,d]pyran-9-one.Following the general workup, the residue passed through a short columnof silica gel and the title compound (4e) was used in the preparation ofthe derivative compound 6e without further purification.

4. 9-Nor-9β-hydroxyhexahydrocannabinol Synthesis

Compound 5

6a,7,8,9,10,10a-Hexahydro-3-(2-hexyl-1,3-dithiolan-2-yl)-6,6-dimethyl-6H-dibenzo[b,d]pyran-1,9β-diol,was synthesized by the method depicted in Scheme 6.

Procedure:

To a stirred solution of(−)-trans-3-(2-hexyl-1,3-dithiolan-2-yl)-6,6a,7,8,10,10a-hexahydro-1-hydroxy-6,6-dimethyl-9H-dibenzo[b,d]pyran-9-one(compound 4c) (1 equiv.) in methanol (approximately 0.05M) at −15° C.under an argon atmosphere was added sodium borohydride (approximately 5equiv.). The reaction was stirred at the same temperature and uponcompletion was quenched by the addition of saturated aqueous ammoniumchloride. The volatiles were removed in vacuo and the residue wasextracted with ethyl acetate. The organic layer was washed with waterand brine, dried over MgSO₄ and the solvent evaporated. The residue waschromatographed on silica gel to afford the title compound in 69% yield.¹H NMR (CDCl₃) δ: 6.70 (d, J=1.7 Hz, 1H, ArH), 6.59 (d, J=1.7 Hz, 1H,ArH), 5.98 (brs, 1H), 3.89-3.84 (m, 1H, H-9), 3.51-3.49 (m, 1H),3.34-3.21 (m, 4H), 2.47 (t, J=10.8 Hz, 1H), 2.30-1.37 (11H, especially1.38, s Me), 1.26-1.16 (m, 8H), 1.06 (s, 3H, Me), 0.84 (t, J=6.9 Hz,3H).

5. 9-Nor-9α-hydroxyhexahydrocannabinol Synthesis

The 9-Nor-9α-hydroxyhexahydrocannabinols (compound 6 with, for example,R groups d and e shown in Scheme 7) were synthesized by a methoddepicted in Scheme 7 below.

General Procedure:

A solution of 9-nor-9-oxohexahydrocannabinol (1 equiv.) in anhydrous THF(approximately 0.02M) was cooled to −78° C. under argon and a 1 Msolution of K-selectride in THF (approximately 5 equiv.) was added in aslow, dropwise manner. The reaction mixture was stirred at −78° C. for2-5 hours and then quenched by cautious addition of water. The mixturewas warmed to room temperature poured into 10% hydrochloric acid and theorganic layer was separated. The aqueous layer was extracted thecombined organic layer dried (MgSO₄) and solvent evaporated. The residuewas chromatographed on silica gel to afford9-Nor-9α-hydroxyhexahydrocannabinols.

Compound 6d

6a,7,8,9,10,10a-Hexahydro-3-(7′-bromo-1′,1′-dimethylheptyl)-6,6-dimethyl-6H-dibenzo[b,d]pyran-1,9α-diol.Yield: 60%. The title compound (6d) was used in the preparation of thederivative compound 7d.

Compound 6e

6a,7,8,9,10,10a-Hexahydro-3-(1′,1′-dimethylhept-6′-ynyl)-6,6-dimethyl-6H-dibenzo[b,d]pyran-1,9α-diol.The title compound (6e) was used in the preparation of the derivativecompound 6f.

FAB HRMS calcd for C₂₄H₃₄O₃ 371.2589 (M+H⁺); found 371.2588.

Compound 6f

6a,7,8,9,10,10a-Hexahydro-3-(7′-tri-n-butyltin-1′,1′-dimethylhept-6′-enyl)-6,6-dimethyl-6H-dibenzo[b,d]pyran-1,9α-diol.

Procedure:

A mixture of3-(1′,1′-dimethylhept-6′-ynyl)-9α-hydroxyhexahydrocannabinol

(Compound 6e)

(100 mg, 0.27 mmol), 1,1′-azobis(cyclohexanecarbonitrile) (20 mg) and0.16 mL of tri-n-butyltin hydride in 5.3 mL of dry toluene was refluxedfor 10 h under argon. The mixture was cooled to room temperature,toluene was removed in vacuo and the residue was chromatographed onsilica gel (30-50% ethyl ether-petroleum ether) to afford 130 mg (73%)of the title compound (6f as a colorless oil.

FAB HRMS calcd for C₃₆H₆₃O₃Sn 663.3799 (M+H⁺); found 663.3798.

6. 9-Nor-9β-azidohexahydrocannabinol Synthesis

The 9-Nor-9β-azidohexahydrocannabinols (compound 7 with, for example, Rgroups d, f and g shown in Scheme 8) were synthesized by the methoddepicted in Scheme 8.

General Procedure:

A mixture of 9-Nor-9α-hydroxyhexahydrocannabinol (1 equiv.), zinc azidebipyridyl complex (approximately 1.5 equiv), triphenylphosphine(approximately, 4 equiv.) anhydrous organic solvent (approximately0.25M) was stirred under argon and a solution of diisopropylazodicarboxylate (DIAD, approximately 4 equiv.) in dry organic solventwas added in slow dropwise manner. The mixture was allowed to stir atroom temperature and upon completion chromatographed on a silica gelcolumn to afford the 9-Nor-9β-azidohexahydrocannabinols.

Compound 7d

1-Hydroxy-3-(7′-bromo-1′,1′-dimethylheptyl)-6,6-dimethyl-9β-azido-6a,7,8,8,10,10a-hexahydro-6H-dibenzo[b,d]pyran.Yield 71%; The title compound (7d) was used in the preparation of thecompound 8.

Compound 7f

1-Hydroxy-3-(7′-tri-n-butyltin-1′,1′-dimethylhept-6′-enyl)-6,6-dimethyl-9β-azido-6a,7,8,8,10,10a-hexahydro-6H-dibenzo[b,d]pyran.Yield 72%; The title compound (7f was used in the preparation of thecompound 9.

Compound 7g

1-Hydroxy-3-(1′,1′-dimethylheptyl)-6,6-dimethyl-9β-azido-6a,7,8,8,10,10a-hexahydro-6H-dibenzo[b,d]pyran.Yield 75%. The precursor for the title compound was synthesized by themethod previously described for compound 6.

IR (AgCl): v=2096 cm⁻¹ (N₃).

The 9-Nor-9β-azidohexahydrocannabinols (compounds 8 and 9 shown inScheme 9) were synthesized by the method depicted in Scheme 9.

Compound 8

1-Hydroxy-3-(7′-iodo-1′,1′-dimethylheptyl)-6,6-dimethyl-9β-azido-6a,7,8,8,10,10a-hexahydro-6H-dibenzo[b,d]pyran.The title compound (8) was synthesized by the method depicted in Scheme9.

Procedure:

100 mg (0.21 mmol) of 9β-azido-3-(7′-bromo-1′,1′-dimethylheptyl)hexahydrocannabinol (compound 7d) was dissolved in 5 ml of dry acetone,63 mg (0.42 mmol) of sodium iodide was added and the solution wasrefluxed for 6 hours. Acetone was removed by rotary evaporation and theresidue was extracted in ether. The ether extract was concentrated andthe residue chromatographed to afford 88 mg (80%) of the title compound(8) as a gum.

Compound 9

1-Hydroxy-3-(7′-iodo-1′,1′-dimethylhept-6′-enyl)-6,6-dimethyl-9β-azido-6a,7,8,8,10,10a-hexahydro-6H-dibenzo[b,d]pyran.The title compound (9) was synthesized by a method depicted in Scheme 9.

Procedure:

16 mg (0.023 mmol) of 9-Nor-9β-azidohexahydrocannabinol (compound 7f)was dissolved in 1 mL of dichloromethane and a solution of 8.7 mg (0.034mmol) of iodine in 0.5 mL of dichloromethane was added dropwise. Thesolution was stirred at room temperature for 15 min and excess iodinewas destroyed by adding a 0.1 M aqueous solution of sodium hydrogensulfite. The organic layer was separated, dried (MgSO₄) and solventremoved. The residue was purified by column chromatography on silica gelto afford 12.8 mg of the title compound (9).

FAB HRMS calc'd for C₂₄H₃₄IN₃O₂ 524.1744 (M+H⁺); found 524.1771.

Generally, the synthesis of compounds 2a-2e, 3, 4a-4e, 5, 6d-6f, 7d-7g,8 and 9 was accomplished by the stereospecific condensation (Scheme 3,Scheme 5) of nopinone diacetates with an appropriately substitutedresorcinol. On the other hand the requisite mixture of nopinonediacetates was prepared by the method disclosed in Drake et al. J. Med.Chem., 3596 (1998). This method involves isopropenyl acetate basedtransesterification followed by lead tetraacetate oxidation with no lossof optical purity starting from commercially available (1R,5S)-(+)-nopinone. Since (1S, 5R)-(−)-nopinone of respectable opticalpurity can be obtained from commercially available (+)-β-pinene or(+)-α-pinene by the method disclosed in Brown et al. J. Org. Chem., 1217(1990) and in Lavalle'e et al. J. Org. Chem., 1362 (1986) respectively,the enantiomers of the above mentioned compounds could be synthesizedfollowing the same methodology. Each of the above references isincorporated by reference herein.

The inventive analogs described herein, and physiologically acceptablesalts thereof, have high potential when administered in therapeuticallyeffective amounts for providing a physiological effect useful to treatpain; peripheral pain; glaucoma; epilepsy; nausea such as associatedwith cancer chemotherapy; AIDS Wasting Syndrome; cancer;neurodegenerative diseases including Multiple Sclerosis, Parkinson'sDisease, Huntington's Chorea and Alzheimer's Disease; to enhanceappetite; to reduce fertility; to prevent or reduce diseases associatedwith motor function such as Tourette's syndrome; to provideneuroprotection; to produce peripheral vasodilation and to suppressmemory. Thus, another aspect of the invention is the administration of atherapeutically effective amount of an inventive compound, or aphysiologically acceptable salt thereof, to an individual or animal toprovide a physiological effect.

Those skilled in the art will recognize, or be able to ascertain with nomore than routine experimentation, many equivalents to the specificembodiments of the invention disclosed herein. Such equivalents areintended to be encompassed by the scope of the invention.

1. A compound of the formula below, and physiologically acceptable saltsthereof:

wherein Y is selected from >C═O, >CH—(CH₂)_(f)—Y₁—(CH₂)_(g)—Y₂, >C═N—Y₃,>CH—NY₄Y₅, >CH—(CH₂)_(h)—Y₆, —C(O)N(Y₇)—, —N(Y₇)C(O)—, >NY₁₁,>N—(CH₂)_(f)—Y₁—(CH₂)_(g)—Y₂, a spirocycle, or CY₉Y₁₀, including allisomers, Y₁ is independently selected from O, CO, C(O)O, OCO or CH₂; Y₂is independently selected from H, halogen, CN, CF₃, N₃, OH, COOH,alkoxy, acyloxy, NCS, NCO or NY₇Y₈; Y₃ is independently selected from—OH, —NH₂, alkoxy, alkyl, —(CH₂)_(n)—NR₁₀R₁₁, —(CH₂)_(n)—CO₂R where R isindependently selected from H, alkyl, —O—(CH₂)_(n)—NR₁₀R₁₁,—O—(CH₂)_(n)—CO₂R or —O—(CH₂)_(n)—CONR₁₀R₁₁; Y₄ is independentlyselected from H, OH, alkoxy or alkyl; Y₅ is independently selected fromH, OH, alkoxy or alkyl, wherein Y₄ and Y₅ cannot both be OH and whereinY₄ and Y₅ cannot both be alkoxy; Y₆ is independently selected from H,halogen, CN, COOH, COalkyl, CF₃, SO₂alkyl, COfluoroalkyl, N₃, OH,alkoxy, acyloxy, NCS, NCO or NY₇Y₈; Y₇ is independently selected from H,alkyl, hydroxyalkyl, an aromatic ring, an aromatic ring substituted byat least one member selected from alkyl, alkoxy, halogen and CF₃, aheterocyclic ring or a heteroaromatic ring; Y₈ is independently selectedfrom H, alkyl, hydroxyalkyl, an aromatic ring, an aromatic ringsubstituted by at least one member selected from alkyl, alkoxy, halogenand CF₃, a heterocyclic ring or a heteroaromatic ring; or alternatively,Y₇ and Y₈ taken together comprise part of a 3 to 7 membered saturatedheterocyclic ring containing up to one additional heteroatom selectedfrom N, O and S; Y₉ is independently selected from H, alkyl oralkoxycarbonylmethyl; Y₁₀ is independently selected from H, alkyl oralkoxycarbonylmethyl; Y₁₁ is independently selected from H, alkyl, CO,CN, CO-alkyl, SO₂-akyl or CF₃; f is an integer from 0 to about 5; g isan integer from 0 to about 5; h is an integer from 0 to about 5; n is aninteger from 0 to about 4; and R₁ and R₂ are each independently selectedfrom H, OH, halogen, alkyl, —O-alkyl, NH₂, NO₂, CN, acyl, aroyl,benzoyl, substituted benzoyl, arylalkyl, substituted arylalkyl,phenacyl, substituted phenacyl, —O-alkyl-NR₁₀R₁₁, —O-alkyl-COOR where Ris selected from H, alkyl, —O-alkyl-CONR₁₀R₁₁, OCOCH₃, —N(alkyl)₂,—CO(alkyl)X or —OCO(alkyl)X where X is selected from H, dialkylamino, acyclic amine, a carbocyclic ring, a heterocyclic ring, an aromatic ringor a heteroaromatic; and R₁₀ and R₁₁ are each independently selectedfrom H, alkyl, hydroxyalkyl or R₁₀ and R₁₁ together comprise part of a 3to 7 membered saturated heterocyclic ring containing up to oneadditional heteroatom selected from N, O and S and R₃ is selected from:

wherein each Z is independently selected from S, O, NH, N(CH₃), SO, SO₂or CR₁₂R₁₃ where R₁₂ and R₁₃ are each independently selected from H oralkyl; R₄ is selected from —(CH₂)_(j)—R₅, —(CH₂)_(j)—A—(CH₂)_(k)—R₅ or—(CH₂)_(j)—A—(CH₂)_(k)—B—R₅; A and B are each independently selectedfrom —CH₂—CH₂—, —CH═CH—, —C≡C—, O, S, SO, SO₂ or NH; R₅ is selected fromH, halogen, CN, CF₃, N₃, COOH, NH₂, N(CH₃)₂, ⊕N(CH₃)₃, Sn(alkyl)₃,phenyl, COOR where R is selected from H or alkyl, a carbocylic ring, aheterocyclic ring, an aromatic ring, a heteroaromatic ring, apolycarbocyclic ring structure having 2 to about 5 rings, apolyheterocyclic ring structure having 2 to about 5 rings or CONR₁₀R₁₁where R₁₀ and R₁₁ are each independently selected from H, alkyl,hydroxyalkyl or R₁₀ and R₁₁ together comprise part of a 5 or 6 memberedsaturated heterocyclic ring containing up to one additional heteroatomselected from N, O and S; n is an integer from 0 to about 4; j is aninteger from 0 to about 7; and k is an integer from 0 to about 7; or R₃is selected from:

wherein R₆ and R₇ are each independently selected from H or alkyl; R₈ is—(CH₂)_(j)—C≡C—(CH₂)_(k)—R₉; R₉ is selected from H, halogen, CN, CF₃,N₃, COOH, NH₂, N(CH₃)₂, ⊕N(CH₃)₃, Sn(alkyl)₃, phenyl, COOR where R isselected from H or alkyl, a carbocylic ring, a heterocyclic ring, anaromatic ring, a heteroaromatic ring, a polycarbocyclic ring structurehaving 2 to about 5 rings, a polyheterocyclic ring structure having 2 toabout 5 rings or CONR₁₀R₁₁ where R₁₀ and R₁₁ are each independentlyselected from H, alkyl, hydroxyalkyl or R₁₀ and R₁₁ together comprisepart of a 5 or 6 membered saturated heterocyclic ring containing up toone additional heteroatom selected from N, O and S; j is an integer from0 to about 7; and k is an integer from 0 to about 7; or R₁ and R₂ areeach independently selected from H, OH, alkyl or alkoxy and R₃ is:

wherein R₁₃ and R₁₄ are each independently selected from H or alkyl; R₁₅is selected from H, halogen, CN, CF₃, N₃, COOH, NH₂, N(CH₃)₂, ⊕N(CH₃)₃,Sn(alkyl)₃, phenyl, COOR where R is selected from H or alkyl, acarbocylic ring, a heterocyclic ring, an aromatic ring, a heteroaromaticring, a polycarbocyclic ring structure having 2 to about 5 rings, apolyheterocyclic ring structure having 2 to about 5 rings, or CONR₁₀R₁₁where R₁₀ and R₁₁ are each independently selected from H, alkyl,hydroxyalkyl or R₁₀ and R₁₁ together comprise part of a 5 or 6 memberedsaturated heterocyclic ring containing up to one additional heteroatomselected from N, O and S; j is an integer from 0 to about 7; and k is aninteger from 0 to about 7; or Y is >CH—(CH₂)_(h)—Y₆; Y₆ is selected fromCN or N₃ and h is an integer from about 1 to about 3, or Y₆ is selectedfrom N₃ and h is an integer from 0 to about 3; R₁ and R₂ are eachindependently selected from H, OH, alkyl or alkoxy; and R₃ is:

wherein R₁₆ is selected from H, halogen, CN, CF₃, N₃, COOH, NH₂,N(CH₃)₂, ⊕N(CH₃)₃, Sn(alkyl)₃, phenyl, COOR where R is selected from Hor alkyl, a carbocylic ring, a heterocyclic ring, an aromatic ring, aheteroaromatic ring, a polycarbocyclic ring structure having 2 to about5 rings, a polyheterocyclic ring structure having 2 to about 5 rings orCONR₁₀R₁₁ where R₁₀ and R₁₁ are each independently selected from H,alkyl, hydroxyalkyl or R₁₀ and R₁₁ together comprise part of a 5 or 6membered saturated heterocyclic ring containing up to one additionalheteroatom selected from N, O and S; and n is an integer from 0 to about7; with the provisos that: if Y is C═O, and R₁ is selected from H, OH,OCH₃, NH₂, O(CH₂)_(n)N(CH3)₂ where n is an integer from 1-3, and

 where n is an integer between 1-3, and R₂ is selected from H, OH,O(CH₂)₁₋₅OH and OCH₃, then R₃ cannot be selected from (CH₂)_(n)C≡CHwhere n is an integer from 3-5, and

 where each X is independently selected from CH₂, O, S and NH and n isan integer from 3-5; and if Y is C═O, and R₁ and R₂ are both OH, then R₃cannot be C(CH₃)₂(CH₂)_(n)CH₃, where n is an integer from 3-5; and if Yis C═O, and one of R₁ or R₂ is H and the other of R₁ or R₂ is OCH3, thenR₃ cannot be (CH₂)_(n)CH₃, where n is an integer from 4-6; and if Y isC═O, and R₁ and R₂ are both OH, then R₃ cannot be (CH₂)_(n)CH₃, where nis an integer from 4-6; and if Y is C═O, and R₁ and R₂ are both OH, thenR₃ can not be —C(CH₃)₂(CH₂)₄—C≡CH; and if Y is C═O, and R₁ and R₂ areboth OH, then R₃ cannot be the structure

where the sum of j and k is equal to 4-9.
 2. The compound of claim 1wherein R₃ is:

wherein each Z is independently selected from S, O, NH, N(CH₃), SO, SO₂or CR₁₂R₁₃ where R₁₂ and R₁₃ are each independently selected from H oralkyl; R₄ is selected from —(CH₂)_(j)—R₅, —(CH₂)_(j)—A—(CH₂)_(k)—R₅ or—(CH₂)_(j)—A—(CH₂)_(k)—B—R₅; A and B are each independently selectedfrom —CH₂—CH₂—, —CH═CH—, —C≡C—, O, S, SO, SO₂ or NH; R₅ is selected fromH, halogen, CN, CF₃, N₃, COOH, NH₂, N(CH₃)₂, ⊕N(CH₃)₃, Sn(alkyl)₃,phenyl, COOR where R is selected from H or alkyl, a carbocylic ring, aheterocyclic ring, an aromatic ring, a heteroaromatic ring, apolycarbocyclic ring structure having 2 to about 5 rings, apolyheterocyclic ring structure having 2 to about 5 rings or CONR₁₀R₁₁where R₁₀ and R₁₁ are each independently selected from H, alkyl,hydroxyalkyl or R₁₀ and R₁₁ together comprise part of a 5 or 6 memberedsaturated heterocyclic ring containing up to one additional heteroatomselected from N, O and S; n is an integer from 0 to about 4; j is aninteger from 0 to about 7; and k is an integer from 0 to about
 7. 3. Thecompound of claim 1 wherein R₃ is:

wherein R₆ and R₇ are each independently selected from H or alkyl; R₈ isselected from —(CH₂)_(j)—C≡C—(CH₂)_(k)—R₉; R₉ is selected from H,halogen, CN, CF₃, N₃, COOH, NH₂, N(CH₃)₂, ⊕N(CH₃)₃, Sn(alkyl)₃, phenyl,COOR where R is selected from H or alkyl, a carbocylic ring, aheterocyclic ring, an aromatic ring, a heteroaromatic ring, apolycarbocyclic ring structure having 2 to about 5 rings, apolyheterocyclic ring structure having 2 to about 5 rings or CONR₁₀R₁₁where R₁₀ and R₁₁ are each independently selected from H, alkyl,hydroxyalkyl or R₁₀ and R₁₁ together comprise part of a 5 or 6 memberedsaturated heterocyclic ring containing up to one additional heteroatomselected from N, O and S; j is an integer from 0 to about 7; and k is aninteger from 0 to about
 7. 4. The compound of claim 1, wherein R₁ and R₂are each independently selected from H, OH, alkyl or alkoxy and R₃ isselected from:

wherein R₁₃ and R₁₄ and are each independently selected from H or alkyl;R₁₅ is selected from H, halogen, CN, CF₃, N₃, COOH, NH₂, N(CH₃)₂,⊕N(CH₃)₃, Sn(alkyl)₃, phenyl, COOR where R is selected from H or alkyl,a carbocylic ring, a heterocyclic ring, an aromatic ring, aheteroaromatic ring, a polycarbocyclic ring structure having 2 to about5 rings, a polyheterocyclic ring structure having 2 to about 5 rings, orCONR₁₀R₁₁ where R₁₀ and R₁₁ are each independently selected from H,alkyl, hydroxyalkyl or R₁₀ and R₁₁ together comprise part of a 5 or 6membered saturated heterocyclic ring containing up to one additionalheteroatom selected from N, O and S; j is an integer from 0 to about 7;and k is an integer from 0 to about
 7. 5. The compound of claim 1wherein Y is >CH—(CH₂)_(h)—Y₆; Y₆ is selected from CN or N₃ and h is aninteger from about 1 to about 3, or Y₆ is N₃ and h is an integer from 0to about 3; R₁ and R₂ are each independently selected from H, OH, alkylor alkoxy; R₃ is:

wherein R₁₆ is selected from H, halogen, CN, CF₃, N₃, COOH, NH₂,N(CH₃)₂, ⊕N(CH₃)₃, Sn(alkyl)₃, phenyl, COOR where R is selected from Hor alkyl, a carbocylic ring, a heterocyclic ring, an aromatic ring, aheteroaromatic ring, a polycarbocyclic ring structure having 2 to about5 rings, a polyheterocyclic ring structure having 2 to about 5 rings orCONR₁₀R₁₁ where R₁₀ and R₁₁ are each independently selected from H,alkyl, hydroxyalkyl or R₁₀ and R₁₁ together comprise part of a 5 or 6membered saturated heterocyclic ring containing up to one additionalheteroatom selected from N, O and S; and n is an integer from 0 to about7.
 6. A pharmaceutical composition containing a therapeuticallyeffective amount of at least one of the compounds of claim 1 in isolatedand purified form and at least one member selected from an excipient, avehicle, an adjuvant, a flavoring, a colorant or a preservative.
 7. Amethod of stimulating cannabinoid receptors in an individual or animalcomprising administering to the individual or animal a pharmaceuticalpreparation containing a therapeutically effective amount of at leastone of the compounds of claim 1 and at least one member selected from anexcipient, a vehicle, an adjuvant, a flavoring, a colorant or apreservative and the compound is in isolated and purified form.
 8. Themethod of claim 7 wherein the compound more selectively binds to the CB2cannabinoid receptors in the individual or animal.
 9. A compound of theformula below, and physiologically acceptable salts thereof:

wherein Y is selected from >C═O, >CH—(CH₂)_(f)—Y₁—(CH₂)_(g)—Y₂, >C═N—Y₃,>CH—NY₄Y₅, >CH—(CH₂)_(h)—Y₆, —C(O)N(Y₇)—, —N(Y₇)C(O)—, >NY₁₁,>N—(CH₂)_(f)—Y₁—(CH₂)_(g)—Y₂, a spirocycle, or CY₉Y₁₀, including allisomers, Y₁ is independently selected from O, CO, C(O)O, OCO or CH₂; Y₂is independently selected from H, halogen, CN, CF₃, N₃, OH, COOH,alkoxy, acyloxy, NCS, NCO or NY₇Y₈; Y₃ is independently selected from—OH, —NH₂, alkoxy, alkyl, —(CH₂)_(n)—NR₁₀R₁₁, —(CH₂)_(n)—CO₂R where R isindependently selected from H, alkyl, —O—(CH₂)_(n)—NR₁₀R₁₁,—O—(CH₂)_(n)—CO₂R or —O—(CH₂)_(n)—CONR₁₀R₁₁; Y₄ is independentlyselected from H, OH, alkoxy or alkyl; Y₅ is independently selected fromH, OH, alkoxy or alkyl, wherein Y₄ and Y₅ cannot both be OH and whereinY₄ and Y₅ cannot both be alkoxy; Y₆ is independently selected from H,halogen, CN, COOH, COalkyl, CF₃, SO₂alkyl, COfluoroalkyl, N₃, OH,alkoxy, acyloxy, NCS, NCO or NY₇Y₈; Y₇ is independently selected from H,alkyl, hydroxyalkyl, an aromatic ring, an aromatic ring substituted byat least one member selected from alkyl, alkoxy, halogen and CF₃, aheterocyclic ring or a heteroaromatic ring; Y₈ is independently selectedfrom H, alkyl, hydroxyalkyl, an aromatic ring, an aromatic ringsubstituted by at least one member selected from alkyl, alkoxy, halogenand CF₃, a heterocyclic ring or a heteroaromatic ring; or alternatively,Y₇ and Y₈ taken together comprise part of a 3 to 7 membered saturatedheterocyclic ring containing up to one additional heteroatom selectedfrom N, O and S; Y₉ is independently selected from H, alkyl oralkoxycarbonylmethyl; Y₁₀ is independently selected from H, alkyl oralkoxycarbonylmethyl; Y₁₁ is independently selected from H, alkyl, CO,CN, CO-alkyl, SO₂-akyl or CF₃; f is an integer from 0 to about 5; g isan integer from 0 to about 5; h is an integer from 0 to about 5; n is aninteger from 0 to about 4; and R₁ and R₂ are each independently selectedfrom H, OH, halogen, alkyl, —O-alkyl, NH₂, NO₂, CN, acyl, aroyl,benzoyl, substituted benzoyl, arylalkyl, substituted arylalkyl,phenacyl, substituted phenacyl, —O-alkyl-NR₁₀R₁₁, —O-alkyl-COOR where Ris selected from H, alkyl, —O-alkyl-CONR₁₀R₁₁, OCOCH₃, —N(alkyl)₂,—CO(alkyl)X or —OCO(alkyl)X where X is selected from H, dialkylamino, acyclic amine, a carbocyclic ring, a heterocyclic ring, an aromatic ringor a heteroaromatic; and R₁₀ and R₁₁ are each independently selectedfrom H, alkyl, hydroxyalkyl or R₁₀ and R₁₁ together comprise part of a 3to 7 membered saturated heterocyclic ring containing up to oneadditional heteroatom selected from N, O and S and R₃ is selected from:

wherein each Z is independently selected from S, O, NH, N(CH₃), SO, SO₂or CR₁₂R₁₃ where R₁₂ and R₁₃ are each independently selected from H oralkyl; R₄ is selected from —(CH₂)_(j)—R₅, —(CH₂)_(j)—A—(CH₂)_(k)—R₅ or—(CH₂)_(j)—A—(CH₂)_(k)—B—R₅; A and B are each independently selectedfrom —CH₂—CH₂—, —CH═CH—, —C≡C—, O, S, SO, SO₂ or NH; R₅ is selected fromH, halogen, CN, CF₃, N₃, COOH, NH₂, N(CH₃)₂, ⊕N(CH₃)₃, Sn(alkyl)₃,phenyl, COOR where R is selected from H or alkyl, a carbocylic ring, aheterocyclic ring, an aromatic ring, a heteroaromatic ring, apolycarbocyclic ring structure having 2 to about 5 rings, apolyheterocyclic ring structure having 2 to about 5 rings or CONR₁₀R₁₁where R₁₀ and R₁₁ are each independently selected from H, alkyl,hydroxyalkyl or R₁₀ and R₁₁ together comprise part of a 5 or 6 memberedsaturated heterocyclic ring containing up to one additional heteroatomselected from N, O and S; n is an integer from 0 to about 4; j is aninteger from 0 to about 7; and k is an integer from 0 to about 7; or R₃is selected from:

wherein R₆ and R₇ are each independently selected from H or alkyl; R₈ is—(CH₂)_(j)—C≡C—(CH₂)_(k)—R₉; R₉ is selected from H, halogen, CN, CF₃,N₃, COOH, NH₂, N(CH₃)₂, ⊕N(CH₃)₃, Sn(alkyl)₃, phenyl, COOR where R isselected from H or alkyl, a carbocylic ring, a heterocyclic ring, anaromatic ring, a heteroaromatic ring, a polycarbocyclic ring structurehaving 2 to about 5 rings, a polyheterocyclic ring structure having 2 toabout 5 rings or CONR₁₀R₁₁ where R₁₀ and R₁₁ are each independentlyselected from H, alkyl, hydroxyalkyl or R₁₀ and R₁₁ together comprisepart of a 5 or 6 membered saturated heterocyclic ring containing up toone additional heteroatom selected from N, O and S; j is an integer from0 to about 7; and k is an integer from 0 to about 7; or R₁ and R₂ areeach independently selected from H, OH, alkyl or alkoxy and R₃ is:

wherein R₁₃ and R₁₄ are each independently selected from H or alkyl; R₁₅is selected from H, halogen, CN, CF₃, N₃, COOH, NH₂, N(CH₃)₂, ⊕N(CH₃)₃,Sn(alkyl)₃, phenyl, COOR where R is selected from H or alkyl, acarbocylic ring, a heterocyclic ring, an aromatic ring, a heteroaromaticring, a polycarbocyclic ring structure having 2 to about 5 rings, apolyheterocyclic ring structure having 2 to about 5 rings, or CONR₁₀R₁₁where R₁₀ and R₁₁ are each independently selected from H, alkyl,hydroxyalkyl or R₁₀ and R₁₁ together comprise part of a 5 or 6 memberedsaturated heterocyclic ring containing up to one additional heteroatomselected from N, O and S; j is an integer from 0 to about 7; and k is aninteger from 0 to about 7; or Y is >CH—(CH₂)_(h)—Y₆; Y₆ is selected fromCN or N₃ and h is an integer from about 1 to about 3, or Y₆ is selectedfrom N₃ and h is an integer from 0 to about 3; R₁ and R₂ are eachindependently selected from H, OH, alkyl or alkoxy; and R₃ is:

wherein R₁₆ is selected from H, halogen, CN, CF₃, N₃, COOH, NH₂,N(CH₃)₂, ⊕N(CH₃)₃, Sn(alkyl)₃, phenyl, COOR where R is selected from Hor alkyl, a carbocylic ring, a heterocyclic ring, an aromatic ring, aheteroaromatic ring, a polycarbocyclic ring structure having 2 to about5 rings, a polyheterocyclic ring structure having 2 to about 5 rings orCONR₁₀R₁₀ where R₁₀ and R₁₁ are each independently selected from H,alkyl, hydroxyalkyl or R₁₀ and R₁₁ together comprise part of a 5 or 6membered saturated heterocyclic ring containing up to one additionalheteroatom selected from N, O and S; and n is an integer from 0 to about7; with the provisos that: if Y is C═O, and R₁ and R² are both OH, thenR³ cannot be the structure

where the sum of j and k is equal to 4-9; and if Y is C═O, and R₁ isselected from H, OH, OCH₃, NH₂, O(CH₂)₁₋₃N(CH3)₂ and

where n is an integer between 1-3, and R₂ is selected from H, OH,O(CH₂)₁₋₅OH and OCH₃, then R₃ cannot be selected from (CH₂)₃₋₅C═CH and

where each X is independently selected from CH₂, O, S and NH and n is aninteger from 3-5; and if Y is C═O, and R₁ and R₂ are both OH, then R₃cannot be C(CH₃)₂(CH₂)₃₋₅CH₃; and if Y is C═O, and one of R₁ or R₂ is Hand the other of R₁ or R₂ is OCH3, then R₃ cannot be (CH₂)₄₋₆CH₃; and ifY is C═O, and R₁ and R₂ are both OH, then R₃ cannot be (CH₂)₄₋₆CH₃; andif Y is C═O, and R₁ and R₂ are both OH, then R₃ can not be—C(CH₃)₂(CH₂)₄—C≡CH.
 10. A compound of the formula below, andphysiologically acceptable salts thereof:

wherein X is selected from >C═O, >CH—(CH₂)_(f)—X₁—(CH₂)_(g)—X₂, >C═N—X₃,>CH—NX₄X₅, >CH—(CH₂)_(h)—X₆, —C(O)N(X₇)—, —N(X₇)C(O)—, >NX₁₁,>N—(CH₂)_(f)—X₁—(CH₂)_(g)—X₂, a spirocycle, or CX₉X₁₀, including allisomers; X₁ is independently selected from O, CO, C(O)O, OCO or CH₂; X₂is independently selected from H, halogen, CN, CF₃, N₃, OH, COOH,alkoxy, acyloxy, NCS, NCO or NX₇X₈; X₃ is independently selected from—OH, —NH₂, alkoxy, alkyl, —(CH₂)_(n)—NR₁₀R₁₁, —(CH₂)_(n)—CO₂R where R isselected from H or alkyl, —O—(CH₂)_(n)—NR₁₀R₁₁, —O—(CH₂)_(n)—CO₂R or—O—(CH₂)_(n)—CONR₁₀R₁₁; X₄ is independently selected from H, OH, alkoxyor alkyl; X₅ is independently selected from H, OH, alkoxy or alkyl,wherein X₄ and X₅ cannot both be OH and wherein X₄ and X₅ cannot both bealkoxy; X₆ is independently selected from H, halogen, CN, COOH, COalkyl,CF₃, SO₂alkyl, COfluoroalkyl, N₃, OH, alkoxy, acyloxy, NCS, NCO orNX₇X₈; X₇ is independently selected from H, alkyl, hydroxyalkyl, anaromatic ring, an aromatic ring substituted by at least one memberselected from alkyl, alkoxy, halogen and CF₃, a heterocyclic ring or aheteroaromatic ring; X₈ is independently selected from H, alkyl,hydroxyalkyl, an aromatic ring, an aromatic ring substituted by at leastone member selected from alkyl, alkoxy, halogen and CF₃, a heterocyclicring or a heteroaromatic ring; or alternatively, X₇ and X₈ takentogether comprise part of a 3 to 7 membered saturated heterocyclic ringcontaining up to one additional heteroatom selected from N, O and S; X₉is independently selected from H, alkyl or alkoxycarbonylmethyl; X₁₀ isindependently selected from H, alkyl or alkoxycarbonylmethyl; X₁₁ isindependently selected from H, alkyl, CO, CN, COalkyl, SO₂alkyl or CF₃;f is an integer from 0 to about 3; g is an integer from 0 to about 3; his an integer from 0 to about 3; n is an integer from 0 to about 4; R₁is independently selected from H, OH, halogen, alkyl, —O-alkyl, NH₂,NO₂, CN, acyl, aroyl, benzoyl, substituted benzoyl, arylalkyl,substituted arylalkyl, phenacyl, substituted phenacyl, —O-alkyl-NR₁₀R₁₁,—O-alkyl-COOR where R is selected from H or alkyl, —O-alkyl-CONR₁₀R₁₁,OCOCH₃, —N(alkyl)₂, —CO(alkyl)X or —OCO(alkyl)X where X is selected fromH, dialkylamino, a cyclic amine, a carbocyclic ring, a heterocyclicring, an aromatic ring or a heteroaromatic; and R₁₀ and R₁₁ are eachindependently selected from H, alkyl, hydroxyalkyl or R₁₀ and R₁₁together comprise part of a 3 to 7 membered saturated heterocyclic ringcontaining up to one additional heteroatom selected from N, O and S; andR₃ is selected from:

wherein each Z is independently selected from S, O, NH, N(CH₃), SO, SO₂or CR₁₂R₁₃ where R₁₂ and R₁₃ are each independently selected from H oralkyl; R₄ is selected from —(CH₂)_(j)—R₅, —(CH₂)_(j)—A—(CH₂)_(k)—R₅ or—(CH₂)_(j)—A—(CH₂)_(k)—B—R₅; A and B are each independently selectedfrom —CH₂—CH₂—, —CH═CH—, —C≡C—, O, S, SO, SO₂ or NH; R₅ is selected fromH, halogen, CN, CF₃, N₃, COOH, NH₂, N(CH₃)₂, ⊕N(CH₃)₃, Sn(alkyl)₃,phenyl, COOR where R is selected from H or alkyl, a carbocylic ring, aheterocyclic ring, an aromatic ring, a heteroaromatic ring, apolycarbocyclic ring structure having 2 to about 5 rings, apolyheterocyclic ring structure having 2 to about 5 rings or CONR₁₀R₁₁where R₁₀ and R₁₁ are each independently selected from H, alkyl,hydroxyalkyl or R₁₀ and R₁₁ together comprise part of a 5 or 6 memberedsaturated heterocyclic ring containing up to one additional heteroatomselected from N, O and S; n is an integer from 0 to about 4; j is aninteger from 0 to about 7; and k is an integer from 0 to about 7; or R₃is:

wherein, R₆ and R₇ are each independently selected from H or alkyl; R₈is —(CH₂)_(j)—C≡C—(CH₂)_(k)—R₉; R₉ is selected from H, halogen, CN, CF₃,N₃, COOH, NH₂, N(CH₃)₂, ⊕N(CH₃)₃, Sn(alkyl)₃, phenyl, COOR where R isselected from H or alkyl, a carbocylic ring, a heterocyclic ring, anaromatic ring, a heteroaromatic ring, a polycarbocyclic ring structurehaving 2 to about 5 rings, a polyheterocyclic ring structure having 2 toabout 5 rings or CONR₁₀R₁₁ where R₁₀ and R₁₁ are each independentlyselected from H, alkyl, hydroxyalkyl or R₁₀ and R₁₁ together comprisepart of a 5 or 6 membered saturated heterocyclic ring containing up toone additional heteroatom selected from N, O and S; j is an integer from0 to about 7; and k is an integer from 0 to about 7; or R₁ isindependently selected from H, OH, alkyl or alkoxy; and R₃ is:

wherein R₁₃ and R₁₄ are each independently selected from H or alkyl; R₁₅is selected from halogen, CN, CF₃, N₃, COOH, NH₂, N(CH₃)₂, ⊕N(CH₃)₃,Sn(alkyl)₃, phenyl, COOR where R is selected from H or alkyl, acarbocylic ring, a heterocyclic ring, an aromatic ring, a heteroaromaticring, a polycarbocyclic ring structure having 2 to about 5 rings, apolyheterocyclic ring structure having 2 to about 5 rings or CONR₁₀R₁₁where R₁₀ and R₁₁ are each independently selected from H, alkyl,hydroxyalkyl or R₁₀ and R₁₁ together comprise part of a 5 or 6 memberedsaturated heterocyclic ring containing up to one additional heteroatomselected from N, O and S; j is an integer from 0 to about 7; and k is aninteger from 0 to about 7; or X is >CH—(CH₂)_(h)—X₆; X₆ is independentlyselected from I, CN, N₃ or COOH and h is an integer from about 1 toabout 3, or X₆ is selected from I, N₃ or COOH and h is an integer from 0to about 3, including all isomers; R₁ is independently selected from H,OH, alkyl or alkoxy; and R₃ is:

wherein R₁₆ is selected from H, halogen, CN, CF₃, N₃, COOH, NH₂,N(CH₃)₂, ⊕N(CH₃)₃, Sn(alkyl)₃, phenyl, COOR where R is selected from Hor alkyl, a carbocylic ring, a heterocyclic ring, an aromatic ring, aheteroaromatic ring, a polycarbocyclic ring structure having 2 to about5 rings, a polyheterocyclic ring structure having 2 to about 5 rings orCONR₁₀R₁₁ where R₁₀ and R₁₁ are each independently selected from H,alkyl, hydroxyalkyl or R₁₀ and R₁₁ together comprise part of a 5 or 6membered saturated heterocyclic ring containing up to one additionalheteroatom selected from N, O and S; and n is an integer from 0 to about7; with the provisos that, X can not be >CH—N₃ when R₁ is OH and R₃ is

wherein R₁₆ is I or N₃ and n is 6; and X₆ can not be I or COOH when X is>CH—(CH₂)_(h)—X₆ and R₃ is

wherein R₁₆ is H; and if X is >C═O and R₁ is OH and R₃ is

 wherein each Z is CH₃, than R₄ can not be H; and if X comprises acarbon ring atom and if R₁ is selected from the group consisting of H,OH, OCH3, NH2 and NHCH3, then R₃ cannot be

wherein each Z is independently selected from the group consisting of S,O, NH, N(CH₃), SO, SO₂ or CH₂; and R₄ is selected from the groupconsisting of H, —OH, —OCH₃, —OCH₂CH₃, halogen, —CN, —N₃, —NCO, —NCS,—CH₃, —CH₂OH, —CH₂OCH₃, —CH₂OCH₂CH₃, —CH₂(halogen), —CH₂CN, —CH₂CH₃,—CH₂NH₂, —CH₂NHCH₃ and —CH₂N(CH₃)₂.
 11. The compound of claim 10 havingthe following structure,


12. The compound of claim 10, wherein R₃ is:

wherein, R₆ and R₇ are each independently selected from H or alkyl; R₈is —(CH₂)_(j)—C≡C—(CH₂)_(k)—R₉; R₉ is selected from H, halogen, CN, CF₃,N₃, COOH, NH₂, N(CH₃)₂, ⊕N(CH₃)₃, Sn(alkyl)₃, phenyl, COOR where R isselected from H or alkyl, a carbocylic ring, a heterocyclic ring, anaromatic ring, a heteroaromatic ring, a polycarbocyclic ring structurehaving 2 to about 5 rings, a polyheterocyclic ring structure having 2 toabout 5 rings or CONR₁₀R₁₁ where R₁₀ and R₁₁ are each independentlyselected from H, alkyl, hydroxyalkyl or R₁₀ and R₁₁ together comprisepart of a 5 or 6 membered saturated heterocyclic ring containing up toone additional heteroatom selected from N, O and S; j is an integer from0 to about 7; and k is an integer from 0 to about
 7. 13. The compound ofclaim 10, R₁ is independently selected from H, OH, alkyl or alkoxy; andR₃ is:

wherein R₁₃ and R₁₄ are each independently selected from H or alkyl; R₁₅is selected from halogen, CN, CF₃, N₃, COOH, NH₂, N(CH₃)₂, ⊕N(CH₃)₃,Sn(alkyl)₃, phenyl, COOR where R is selected from H or alkyl, acarbocylic ring, a heterocyclic ring, an aromatic ring, a heteroaromaticring, a polycarbocyclic ring structure having 2 to about 5 rings, apolyheterocyclic ring structure having 2 to about 5 rings or CONR₁₀R₁₁where R₁₀ and R₁₁ are each independently selected from H, alkyl,hydroxyalkyl or R₁₀ and R₁₁ together comprise part of a 5 or 6 memberedsaturated heterocyclic ring containing up to one additional heteroatomselected from N, O and S; j is an integer from 0 to about 7; and k is aninteger from 0 to about
 7. 14. The compound of claim 10 wherein: X is>CH—(CH₂)_(h)—X₆; X₆ is independently selected from I, CN, N₃ or COOHand h is an integer from about 1 to about 3, or X₆ is selected from I,N₃ or COOH and h is an integer from 0 to about 3, including all isomers;R₁ is independently selected from H, OH, alkyl or alkoxy; and R₃ is:

wherein R₁₆ is selected from H, halogen, CN, CF₃, N₃, COOH, NH₂,N(CH₃)₂, ⊕N(CH₃)₃, Sn(alkyl)₃, phenyl, COOR where R is selected from Hor alkyl, a carbocylic ring, a heterocyclic ring, an aromatic ring, aheteroaromatic ring, a polycarbocyclic ring structure having 2 to about5 rings, a polyheterocyclic ring structure having 2 to about 5 rings orCONR₁₀R₁₁ where R₁₀ and R₁₁ are each independently selected from H,alkyl, hydroxyalkyl or R₁₀ and R₁₁ together comprise part of a 5 or 6membered saturated heterocyclic ring containing up to one additionalheteroatom selected from N, O and S; and n is an integer from 0 to about7.
 15. The compound of claim 10, wherein R₃ is

wherein each Z is independently selected from S, O, NH, N(CH₃), SO, SO₂or CR₁₂R₁₃ where R₁₂ and R₁₃ are each independently selected from H oralkyl; R₄ is selected from —(CH₂)_(j)—R₅, —(CH₂)_(j)—A—(CH₂)_(k)—R₅ or—(CH₂)_(j)—A—(CH₂)_(k)—B—R₅, A and B are each independently selectedfrom —CH₂—CH₂—, —CH═CH—, —C≡C—, O, S, SO, SO₂ or NH; R₅ is selected fromH, halogen, CN, CF₃, N₃, COOH, NH₂, N(CH₃)₂, ⊕N(CH₃)₃, Sn(alkyl)₃,phenyl, COOR where R is selected from H or alkyl, a carbocylic ring, aheterocyclic ring, an aromatic ring, a heteroaromatic ring, apolycarbocyclic ring structure having 2 to about 5 rings, apolyheterocyclic ring structure having 2 to about 5 rings or CONR₁₀R₁₁where R₁₀ and R₁₁ are each independently selected from H, alkyl,hydroxyalkyl or R₁₀ and R₁₁ together comprise part of a 5 or 6 memberedsaturated heterocyclic ring containing up to one additional heteroatomselected from N, O and S; n is an integer from 0 to about 4; j is aninteger from 0 to about 7; and k is an integer from 0 to about
 7. 16. Apharmaceutical composition containing a therapeutically effective amountof at least one of the compounds of claim 10 in isolated and purifiedform and at least one member selected from an excipient, a vehicle, anadjuvant, a flavoring, a colorant or a preservative.
 17. A method ofstimulating cannabinoid receptors in an individual or animal comprisingadministering to the individual or animal a pharmaceutical preparationcontaining a therapeutically effective amount of at least one of thecompounds of claim 10 and at least one member selected from anexcipient, a vehicle, adjuvant, a flavoring, a colorant or apreservative and the compound is in isolated and purified form.
 18. Themethod of claim 17 wherein the compound more selectively binds to theCB2 cannabinoid receptors in the individual or animal.
 19. The compoundof claim 1 wherein R₃ is


20. The compound of claim 10 wherein R₃ is